Biodegradable polymers have been fabricated into various biomedical implants such as drug delivery nanoparticles, tissue engineering scaffolds, and orthopedic devices. Using biodegradable polymers as implant materials is beneficial as the implants may be degraded and cleared by the body once their missions are complete, leaving no foreign materials in the body. On the other hand, florescent labeling and imaging have fueled the significant growth of life science and medical research due to the increasing demands on analyzing biomolecules, tracking biological process, and visualizing diseases and therapeutic efficacy. The most common fluorescent imaging agents include organic dyes, fluorescent proteins and quantum dots (QDs). The discovery of fluorescent QDs has revolutionized the field of molecular imaging, especially in oncology applications. However, progress made in the past has not alleviated much on their high cost and intrinsic toxicity concerns which substantially hinder their clinical use in patients. As alternatives, fluorescent dyes suffer from photobleaching and fluorescent proteins are dim in vivo and hard to manipulate. It is noteworthy that all the above imaging agents are just "imaging agents". They cannot act alone as medical implants to serve as drug delivery vehicles or tissue engineering scaffolds. Combining biomedical implants and imaging agents for drug delivery and tissue engineering has been a significant focus of research in the past few years. For drug delivery, a significant challenge is to develop multifunctional nanoparticles that can be used to track drug delivery processes and determine therapeutic efficiency in real-time. Although conjugating organic dyes to, or encapsulating QDs in, biodegradable polymers was considered as a significant step in addressing above challenges, it does not address the concerns on their toxicity and low dye-to- nanoparticle labeling ratio for in vivo applications. For tissue engineering, obtaining in-situ and real-time information on scaffold degradation and tissue infiltration/regeneration in vivo, without traumatically explanting samples or sacrificing animals, is an unaddressed challenge. Using safe biodegradable implant polymers that intrinsically emit detectable fluorescence in vivo would address the above challenges in drug delivery and tissue engineering, as well as open new windows for other biological and biomedical applications based on fluorescence labeling and imaging. However, such biomaterials have not been available. Therefore, the objectives of the proposed work are to 1) discover novel in-vivo safe, wholly-biodegradable, photoluminescent (implant) polymers (BPLP), without conjugating organic dyes or semiconducting quantum dots (QDs), and 2) to develop biodegradable polymeric "QDs" (BPLP nanoparticles) promising for bioimaging, exemplified by in vivo breast cancer targeting and imaging. The expected outcomes of the proposed work are that we will understand the mechanisms behind the unique photoluminescent properties of BPLPs, and that we will establish a methodology to expand the BPLP into different types of biodegradable implant polymers. We will demonstrate their novelty and utility by developing biodegradable BPLP nanoparticles (biodegradable polymeric "QDs") for cell labeling and imaging applications, exemplified by cancer cell targeting and imaging in vivo. The Impacts of this proposal lie in that: 1) Unveiling the intriguing fluorescence mechanism and the methods necessary for the syntheses of biodegradable photoluminescent polymers will significantly advance biomaterials science;and 2) the development of BPLPs should bring a paradigm shift in the use of biodegradable implant biomaterials in a broad range of biological and biomedical fields including biosensing, cellular imaging, drug delivery, tissue engineering, and theranostic nanomedicine. PUBLIC HEALTH RELEVANCE: The success of this proposal will result in the discovering and understanding the only kind of biodegradable photoluminescent polymers (BPLPs) that intrinsically emit detectable fluorescence from the body. Based on our recent exciting development on BPLPs, we propose to further unveil the intriguing fluorescence mechanism of BPLPs and develop a methodology for custom-designing multiple classes of BPLPs to meet the versatile needs in biology and medicine. We will also demonstrate BPLP nanoparticles (biodegradable polymeric "quantum dots") as safe in vivo imaging probes for cancer targeting and imaging. Traditional imaging agents such as organic dyes or quantum dots (QDs) are just "imaging agents". They cannot act as implant materials such as drug delivery vehicles or tissue engineering scaffolds. BPLPs are the only polymeric biomaterials that can serve as not only in vivo safe implant materials but also in vivo fluorescent imaging probes without incorporating traditional organic dyes or QDs thus eliminating concerns on photobleaching, low dye-conjugation ratio, and toxicity for in vivo medical applications. The success of this proposal will innovate the biodegradable implant polymers, result in new tools and methods for tracking drug delivery process and therapeutic efficacy, and monitoring structure, composition, and function of engineered tissues in real time quantitatively and non-invasively. The development of BPLPs will have huge impacts on a broad range of fields in biology and medicine including biosensing, cellular imaging, drug delivery, tissue engineering, and theranostic nanomedicine.